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Colorectal Cancer Recurrence Predicted Early by Methylation-Based Liquid Biopsy Test

NEW YORK – New research suggests DNA methylation markers in circulating tumor DNA (ctDNA) can help to identify colorectal cancer (CRC) patients at increased risk of disease recurrence early who may benefit from more intensive treatment regimens.

The markers can potentially help doctors make decisions, "especially for postoperative patient selection for [adjuvant chemotherapy], assessment of duration and intensity of treatment, and prognostic patient care," co-senior and co-corresponding author Guoxiang Cai, a researcher with Fudan University's colorectal surgery department and the Fudan University Shanghai Cancer Center, said in an email.

For a multicenter prospective study published in JAMA Oncology on Thursday, the researchers used a multi-locus qPCR assay dubbed ColonAiQ to search for half a dozen DNA methylation-based CRC ctDNA markers in more than 1,200 blood samples from 299 individuals with stage I to stage III CRC, including samples collected before and after surgery, as well as after treatment, including adjuvant chemotherapy, if applicable.

Based on samples collected every three months for up to two years, the team found that the methylation-based ctDNA detection approach picked up CRC cases with residual disease after surgery or adjuvant chemotherapy after therapy, pointing to the possibility of using methylation markers for cost-effective disease monitoring.

The results suggested that "longitudinal changes of ctDNA methylation are effective to monitor disease progression from MRD to recurrence," Cai explained, noting that the team's clinicopathological risk assessment analysis suggested that ctDNA methylation "was the most significant prognostic factor of recurrence-free survival."

In particular, the presence of ctDNA a month after surgery — detected using methylation markers — coincided with poorer disease-free survival outcomes, the researchers reported, noting that they saw a similar prognostic relationship between ctDNA and disease recurrence in patients who went on to receive adjuvant chemotherapy.

Overall, the team saw disease recurrence in 55 of the CRC patients, representing more than 18 percent of the study participants. Those relapses were more common in individuals with ctDNA-positive blood samples before surgery and a month out from surgery.

In 296 available pre-operative samples, ctDNA methylation markers turned up in more than 78 percent of individuals, the researchers reported, including just over 65 percent of samples from stage I cases, nearly 83 percent of stage II cases, and almost 82 percent of stage III cases.

Specifically, ctDNA was found in pre-surgery blood samples from more than 94 percent of the individuals who went on to experience disease recurrence, compared to just one-quarter of the pre-operative samples from individuals who remained recurrence-free over the study's follow-up time. In contrast, more than 95 percent of patients who had ctDNA-negative samples prior to surgery remained free of disease over the course of the study.

In blood samples collected a month after surgery from 255 of the CRC patients, they found that nearly 77 percent had undetectable ctDNA methylation, and 94.4 percent of those patients were disease-free during the study's follow-up time. In contrast, recurrence occurred in 66 percent of patients who were ctDNA-positive at the one-month post-surgery point.

Together, the authors estimated that ctDNA methylation tests a month after surgery could predict relapse with 78 percent sensitivity and more than 90 percent specificity.

Past research suggests nearly one-third of CRC cases return after therapy, Cai explained, making it particularly important to distinguish between high-risk, recurrence-prone cases that require additional therapy and those that can forego toxicities associated with treatments such as chemotherapy.

While ctDNA has become a promising avenue for monitoring minimal residual disease (MRD), approaches that rely on tumor mutation detection can become costly and are not easily transferred from one patient to the next, prompting investigators involved in the current study to focus on DNA methylation features that may be more common across CRC tumors.

In a related JAMA Oncology editorial, Ajay Goel, a researcher at the City of Hope Comprehensive Cancer Center and the Beckman Research Institute of City of Hope, and Juan Ruiz-Bañobre, with the University of Santiago de Compostela in Spain, noted that "there is substantial value in prospectively validating the clinical importance of ColonAiQ in randomized clinical trials."

"If successful," they explained, "this liquid biopsy assay could represent a simple and cost-effective means for a more accessible and facile decentralized implementation in routine clinical practice."